Interplay of reactive oxygen species, intracellular Ca2+ and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin

Kwang Youn Kim, Hyo Jin Cho, Sun Nyoung Yu, Sang Hun Kim, Hak Sun Yu, Yeong Min Park, Nooshin Mirkheshti, So Young Kim, Chung Seog Song, Bandana Chatterjee, Soon Cheol Ahn

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40 Scopus citations

Abstract

The limited treatment option for recurrent prostate cancer and the eventual resistance to conventional chemotherapy drugs has fueled continued interest in finding new anti-neoplastic agents of natural product origin. We previously reported anti-proliferative activity of deoxypodophyllotoxin (DPT) on human prostate cancer cells. Using the PC-3 cell model of human prostate cancer, the present study reveals that DPT induced apoptosis via a caspase-3-dependent pathway that is activated due to dysregulated mitochondrial function. DPT-treated cells showed accumulation of the reactive oxygen species (ROS), intracellular Ca i2+ surge, increased mitochondrial membrane potential (MMP, ΔΨm), Bax protein translocation to mitochondria and cytochrome c release to the cytoplasm. This resulted in caspase-3 activation, which in turn induced apoptosis. The antioxidant N-acetylcysteine (NAC) reduced ROS accumulation, MMP and Ca i2+ surge, on the other hand the Ca2+ chelator BAPTA inhibited the Ca i2+ overload and MMP without affecting the increase of ROS, indicating that the generation of ROS occurred prior to Ca 2+ flux. This suggested that both ROS and Ca i2+ signaling play roles in the increased MMP via Ca i2+-dependent and/or -independent mechanisms, since ΔΨm elevation was reversed by NAC and BAPTA. This study provides the first evidence for the involvement of both ROS- and Ca i2+-activated signals in the disruption of mitochondrial homeostasis and the precedence of ROS production over the failure of Ca2+ flux homeostasis.

Original languageEnglish (US)
Pages (from-to)1124-1134
Number of pages11
JournalJournal of Cellular Biochemistry
Volume114
Issue number5
DOIs
StatePublished - May 1 2013

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Keywords

  • Ca overload
  • apoptosis
  • deoxypodophyllotoxin (DPT)
  • mitochondrial membrane potential (MMP)
  • reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kim, K. Y., Cho, H. J., Yu, S. N., Kim, S. H., Yu, H. S., Park, Y. M., Mirkheshti, N., Kim, S. Y., Song, C. S., Chatterjee, B., & Ahn, S. C. (2013). Interplay of reactive oxygen species, intracellular Ca2+ and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin. Journal of Cellular Biochemistry, 114(5), 1124-1134. https://doi.org/10.1002/jcb.24455